Neurobehavioral deficits in db/db diabetic mice
Research Highlights
►This is the first report of behavioral depression in db/db mouse strain. ►We also report for the first time age-dependent advancement of psychosis-like symptoms in db/db mice. ►db/db mice were less anxious compared to age-matched lean control mice. ►Working memory performance of db/db mice was not different from lean control mice. ►We speculate that db/db mouse strain can serve as useful preclinical model to study type-2 diabetes related neurobehavioral complications.
Introduction
Comorbid neurobehavioral disturbances in the type-2 diabetic population are emerging problems that warrant immediate research attention. The major concerns of comorbid neurobehavioral deficits in the diabetic population are a dramatic rise in mortality rate and substantial impact on the medical cost to the patient. Although comorbidity of neurobehavioral disturbances and type-2 diabetes in clinical practice is evident, it has not been studied comprehensively in preclinical setting. Significant research emphasis is given to the macrovascular and microvascular complications of diabetes [1], [2], [3], [4], [5]. Recent data also advocate the central nervous system (CNS) as a crucial target for diabetic complications [6]. For instance, the probability of major depression in diabetic patients is approximately double that of those without diabetes [7]. Further, among diabetic patients, those with comorbid depression are at greater risk of mortality and have twice the probability of cardiovascular risk factors like smoking, obesity and sedentary lifestyle [8]. To date, the majority of preclinical investigations studying interrelationships between diabetes and the CNS focused in principal on type-1 diabetes [9].There are a few clinical reports that showed an association between diabetes and CNS complications that are most prominent in elderly type-2 diabetic patients [10]. There is a need to study CNS complications in type-2 diabetes animal models.
The diabetic mouse strain db/db harbors an autosomal recessive point mutation in gene encoding for the long isoform (LRb) of leptin receptor [11], [12]. It was first witnessed by Hummel and colleagues in C57BL/KsJ strain at Jackson Laboratory [13]. Phenotypes of db/db mice mimics clinical type-2 diabetic conditions such as obesity, hyperglycemia, hyperinsulinemia, hyperphagia, polydypsia, polyurea, impotency, pancreatic β-cell hyperplasia and hypertrophy [14]. At early ages, they serve as a good model of type-2 diabetes, characterized by hyperinsulinemia, obesity and progressive hyperglycemia [15]. Hyperinsulinemia occurs as early as ten days of age, peaks at 3 months of age and then gradually declines to near normal values in the mature adult [15]. Blood glucose levels are slightly elevated by 6 weeks and reaches values of ~ 315 mg/dL, followed by ~ 550 mg/dL by 8 weeks [4] and as high as 600 mg/dL by 16 weeks of age [16]. Hitherto, this mouse strain is extensively used as a murine model for evaluating mechanisms of diabetes and to study the cardiovascular, renal and ocular complications of diabetes [17], [18], [19]. However, there is a paucity of research evidence that characterized this mouse strain for its neurobehavioral deficits [20], [21], [22], [23], [24], [25], [26], [27], [28]. Li and colleagues reported impaired spatial memory function and impairment of long-term potentiation (LTP) of memory in db/db mice using Morris water maze test [22]. A conditioned taste aversion (CTA) learning test in the same strain by Ohta and co-workers suggested no impairment in acquisition but extinction of CTA learned behavior compared to age-matched lean littermates [23]. Moreover, changes in the sleep-wake regulation pattern, locomotor activity [21], nociception [26], feeding behavior and body temperature regulation [20], [25] are reported in the db/db mouse strain.
Interestingly, there is widespread distribution of long isoform of leptin receptors (LRb) in key brain regions [29]. Some of these regions, e.g. hypothalamic arcuate nucleus, paraventricular hypothalamic nucleus, dorsomedial hypothalamic nucleus and brainstem nucleus of the solitary tract modulate satiety. On the other hand, the mesolimbic dopamine system's ventral tegmental area and substantia nigra with projections to striatum and amygdala also express leptin receptors [30]. While the nigrostiratal system is involved in locomotor activity, the amygdala is believed to be involved in threat identification and assignment of emotional value to new neutral stimuli. Brain regions modulating depressive symptoms e.g. serotonergic raphe nuclei [31] and anxiety behavior, e.g. amygdala were reported to express leptin receptors [32]. In addition, the hippocampus, an anatomical site that governs cognitive functions and spatial learning, express LRb receptor isoform. Regions of the cerebral cortex that are involved in regulation of mood and emotions showed presence of leptin receptors. Several other regions with less understood LRb function also express this particular receptor isoform [33]. Pharmacological and pathological manipulation of endogenous plasma and brain leptin concentration is reported in many neuropsychiatric disorders and after treatment with several drug classes that can affect brain functions [34], [35], [36], [37]. Lower brain weights, reduced cortical volume and decrease in total glial and neuronal protein expressions were reported in leptin deficient ob/ob mice and similar effects on protein content and brain weights were observed in db/db mice [38]. Recently, Stranahan and colleagues reported diabetes-induced detrimental effects on hippocampal neuronal dendrite morphology and their recovery post-calorie restriction as well as after increased energy expenditure in db/db mice [28]. Interestingly, leptin can also alter neuronal dendrite morphology [39]. Increase in the concentration of gray matter in the anterior cingulate gyrus was reported in genetically leptin-deficient patients when subjected to leptin treatment [40]. Neonatal and maternal leptin treatments are reported to prevent the appearance of adverse metabolic phenotypes [41]. Intrigued with these reports, the present study evaluated db/db mouse strain for presence of neurobehavioral deficits employing paradigms for behavioral depression, psychosis-like symptoms, anxiety, alterations in motor behavior, thigmotaxis and impairments in working memory.
Section snippets
Materials and methods
Male db/db mice (4 week old) with background strain C57BL/KsJ (BKS-Cg-Dock7m +/+ Leprdb/J) and their age-matched non-diabetic lean control mice were purchased from Jackson Laboratories, Bar Harbor, ME, USA. All the mice were singly housed in plastic cages with wooden shavings in a temperature controlled room (22–23 °C) with 12:12 h light : dark cycle (lights off from 1700). Principles of laboratory animal care followed and all experimental protocols were approved by the Wright State University
Metabolic parameters
As shown in Table 1, the blood glucose concentrations of db/db mice were significantly higher compared to age-matched lean controls (p < 0.05, unpaired t-test). There was an age-dependent increase in the blood glucose concentration of db/db mice (juvenile: 230.38 ± 13.25 mg/dL versus adult: 583.20 ± 35.86 mg/dL). However, blood glucose concentrations of lean control mice remained fairly constant (p > 0.05). Food intake, water intake, plasma insulin and % fat mass of db/db mice were significantly
Discussion
The present study is the first report of behavioral depression, age-related advancement of psychosis-like symptoms and anxiolytic behavior in db/db mice. We also observed locomotor deficits in this mouse strain but there were no changes in working memory performance of db/db mice compared to lean controls. The neuropsychological consequences of diabetes are studied with reasonable detail in the clinical setting. However, there is still a scarcity of preclinical research supporting correlations
Acknowledgements
The authors acknowledge the financial support of the AHA SDG 0735112N and the NIH R01 HL093567 (K.M.E.).
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2022, Brain Research BulletinCitation Excerpt :They serve as an excellent model of type 2 diabetes mellitus at an early age, which is characterized by hyperinsulinemia, obesity, and increasing hyperglycemia. As with earlier publications (Sharma et al., 2010, 2012), our investigation indicated that db/db mice displayed obesity, hyperglycemia, hyperinsulinemia, cognitive impairment, and depression-like behavior. Therefore, in our investigation, we used the db/db mouse model to conduct our experiment.